Sodium hydride → 1,1-Dimethylethyl (3S)-3-{[(7-chloro-1,6-naphthyridin-5-yl)oxy]methyl}-3-fluoro-1-piperidinecarboxylate

HRID 473323Notes

Reaction equation

HRID 473323 reaction equation
[F:1][C@@:2]1([CH2:15][OH:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:20]1[N:29]=[C:28]([Cl:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>CN(C=O)C.C(Cl)Cl>[Cl:30][C:28]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[C:20]([O:16][CH2:15][C@:2]2([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]2)[N:29]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 122042335,7-Dichloro-1,6-naphthyridineHCID 68209884tert-butyl (3S)-3-fluoro-3-(hydroxymethyl)piperidine-1-carboxylate

Product 1

HCID 866768021,1-Dimethylethyl (3S)-3-{[(7-chloro-1,6-naphthyridin-5-yl)oxy]methyl}-3-fluoro-1-piperidinecarboxylateYield 80%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To an ice cooled solution of 1,1-dimethylethyl (3S)-3-fluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (1.406 g, 6.03 mmol) in DMF (20 ml) was added sodium hydride (0.313 g, 7.84 mmol) (60% dispersion in mineral oil). This was stirred for 15 min before adding 5,7-dichloro-1,6-naphthyridine (1.2 g, 6.03 mmol). This was warmed to room temp and stirred for 4 h. The reaction had gone to completion and so was cautiously quenched with aqueous ammonium chloride before partitioning between aqueous ammonium chloride and ethyl acetate. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine and concentrated in vacuo to give the crude product. This was dissolved in DCM and purified through silica (50 g), eluting with a gradient of 0-50% ethyl acetate in DCM. Appropriate fractions were concentrated in vacuo to yield the title compound as a cream foamy gum (1.91 g).

Workup

  1. stirringstirred for 4 h
  2. customso was cautiously quenched with aqueous ammonium chloride
  3. custombefore partitioning between aqueous ammonium chloride and ethyl acetate
  4. customThe layers were separated
  5. extractionthe aqueous was re-extracted with ethyl acetate
  6. washThe combined organics were washed with brine
  7. concentrationconcentrated in vacuo
  8. customto give the crude product
  9. custompurified through silica (50 g)
  10. washeluting with a gradient of 0-50% ethyl acetate in DCM
  11. concentrationAppropriate fractions were concentrated in vacuo

Sources & evidence

ORD record
ord-c22231d146d941a9a0057134048661a3
Source dataset
uspto-grants-2014_01
Patent number
US08633319B2

Reaction notes

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